Apparatus and methods for calibrating and/or validating pulmonary function test equipment

ABSTRACT

The present invention relates to quality control of pulmonary function test (PFT) devices. In particular, but not by way of limitation, the present invention relates to systems and methods for characterizing or verifying the measurement accuracy of pulmonary function testing devices used for measuring dynamic lung volumes (tidal volume (TV), inspiratory reserve volume (IRV), expiratory reserve volume (ERV), divisions thereof, and any other suitable dynamic lung volume) using spirometry, static and/or absolute lung volumes (total lung capacity (TLC), residual volume (RV), divisions thereof, and any other suitable absolute lung volume) using washout, dilution, and/or plethysmographic methods, and/or gas exchange, such as single-breath determination of carbon monoxide uptake in the lung (DLCO).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.16/277,141, filed Feb. 15, 2019, which is a division of U.S. patentapplication Ser. No. 15/995,821, filed Jun. 1, 2018, now issued U.S.Pat. No. 10,206,608, which is a non-provisional of, and claims thebenefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional PatentApplication No. 62/513,665, filed Jun. 1, 2017, entitled “Apparatus andMethod for Calibrating and/or Validating Pulmonary Function TestEquipment,” the disclosure of which is hereby incorporated by referencein its entirety

FIELD OF THE INVENTION

The present invention relates to quality control of pulmonary functiontest (PFT) devices. In particular, but not by way of limitation, thepresent invention relates to systems and methods for characterizing orverifying the measurement accuracy of pulmonary function testing devicesused for measuring dynamic lung volumes (tidal volume (TV), inspiratoryreserve volume (IRV), expiratory reserve volume (ERV), divisionsthereof, and any other suitable dynamic lung volume) using spirometry,static and/or absolute lung volumes (total lung capacity (TLC), residualvolume (RV), divisions thereof, and any other suitable absolute lungvolume) using washout, dilution, and/or plethysmographic methods, and/orgas exchange, such as single-breath determination of carbon monoxideuptake in the lung (D_(LCO)).

BACKGROUND

Performing a pulmonary function test (PFT) generally involves the use ofinstrumentation operable to measure physiologic respiratory volume(s)and/or respiratory gas exchange. PFT instruments (also referred toherein as PFT equipment or devices) can include testing capability fordynamic lung volumes, static and/or absolute lung volumes (and relatedparameters) using washout, dilution, and/or plethysmographic methods,and/or measures of gas exchange such as calculated transfer factor(D_(LCO)) and related primary measured parameters and relatedphysiologic tests. Spirometry parameters are typically measured with gasflow sensors using a variety of technologies. In the case of washouttechniques, static and absolute lung volume parameters are typicallymeasured with gas analyzers measuring inhaled and exhaled CO₂ and O₂ gasconcentrations in conjunction with the aforementioned gas flowmeasurements. Plethysmographic methods of measuring static and absolutelung volume parameters typically utilize flow and pressure sensors.Calculation of gas exchange parameters are based on gas analyzermeasurements of inhaled and exhaled CO and a non-diffusing tracer gas,such as CH₄ or He, in conjunction with the aforementioned gas flowmeasurements. Commercially available PFT instruments used for staticlung volume and/or gas exchange measurements typically provide a testgas from a high-pressure source that is regulated to atmosphericpressure for delivery to patients using a regulator (e.g., a demandvalve).

To assure accurate and/or precise measurements, it is desirable toverify and/or calibrate PFT instruments periodically and/or prior topatient use. Such verification and/or calibration can serve to confirm,for example, that the PFT instrument conforms to the statedmanufacturer's performance specifications. The present applicationrelates generally to a means and apparatus to verify and/or calibrate aPFT instrument to its stated manufacturer's specifications in a clinicalenvironment.

Verifying PFT instrumentation generally refers to subjecting theinstrument to a known standard, reference volume, and/or known standard,reference concentration, of test gases, including air at ambienttemperature and pressure, and verifying that the PFT equipment returns avalue consistent with the known volume reference and/or known gasconcentration reference.

Calibrating PFT instrumentation generally refers to adjusting parametersof the PFT instrument in response to subjecting the PFT instrument to aknown standard volume and/or known standard concentrations of a testgases such that the PFT instrument returns a value consistent with theknown volume and/or gas concentration. Commonly available PFTinstruments are typically calibrated at the time of manufacture and/orby trained service technicians and verified by end-users and/or medicalprofessionals under normal operating conditions in the patient testingenvironment.

It is further desirable for PFT instruments to verifiably providephysiologically and/or clinically representative data. To verify thatPFT instruments have sufficient accuracy and/or precision to providephysiologically representative and/or clinically meaningful data, it isdesirable to calibrate and/or validate PFT instruments to minimumclinical accuracy requirements such as those set by peer societies, inparticular the Joint American Thoracic Society and European RespiratorySociety guidelines for the standardization of lung function testing inthe patient testing (clinical) environments.

Generally, validation and/or calibration techniques applied to PFTinstruments involves passing a known volume of gas and/or one or moregas mixtures having a known concentration or ratio of concentrations ofa test gas to the PFT instrument. Existing methods for validating and/orcalibrating PFT instruments include:

-   -   1. Utilizing a person with a known transfer capacity as a        measurement reference.    -   2. Utilizing a device that delivers known gas volumes and/or at        least two gas mixtures from individual sources having differing,        but known, concentrations of a test gas.    -   3. Utilizing a device that delivers known gas volumes and at        least two gas mixtures having known concentrations of the test        gas by diluting one gas mixture into another. For example, U.S.        Pat. No. 9,186,090, which is hereby incorporated by reference in        its entirety, describes some methods and apparatus for diluting        one gas mixture into another to validate and/or calibrate        D_(LCO) capable PFT equipment.        Such methods are generally unable to calibrate and/or validate        PFT instruments to minimum clinical standards and/or        manufacturers' specifications, particularly in a clinical        environment.

Regarding spirometry measurements: current minimum clinical volumeaccuracy requirements of PFT instruments requires measured volumes bewithin +/−2% or 50 mL (whichever is greater) of expected over a volumerange of 0.5 L to 8 L and within flow rates up to 14 L/Sec. The currentindustry standard volume reference used to verify PFT instruments in thefield is a gas syringe that displaces relatively large volumes of gas,such as three to nine liters of gas. During verification or calibrationprocedures, the syringe is commonly subject to heating and coolingsources typically found in patient testing environments, such as HVAC,direct sunlight, or body heat from direct contact of a user.Consequently, using existing devices and practices, the volume deliveredby the syringe deviates from its certified value to levels that renderit insufficient to verify the manufacturer's specifications or minimalclinical accuracy requirements, whichever is better. For example, atemperature difference of as little as 3° C. between the gas temperaturewithin the volume reference standard device and ambient gas temperaturewill introduce an error of approximately 1% into the reference volume.

Regarding absolute and static lung volume measurements utilizingnitrogen washout methods: current minimum clinical volume accuracyrequirements of PFT instruments requires measured volume accuraciescommensurate with spirometry as described above while delivering O₂ testgas at atmospheric pressure to a patient. Accuracy of current volumereference standards are subject to the same limitations as describedabove. A further limitation is that existing volume reference standardsdo not provide a physiologically representative dynamic compliance as aload to the PFT instrument when inspiring test gas from a regulatedhigh-pressure gas source, which can render the simulated PFT volumemeasurement invalid, regardless of its delivered volume accuracy.

Regarding gas exchange measurements: current minimum clinical volumeaccuracy requirements of PFT instruments measuring single-breathdetermination of carbon monoxide uptake in the lung (D_(LCO)) arecommensurate with the standards for absolute and static lung volumemeasurements as described above. In addition to the volume accuracyrequirements, achieving the clinical accuracy requirements of theD_(LCO) parameter (+/−2 mL/min/mmHg @2σ) requires gas analyzermeasurements to be linear within +−0.75% of their full scale range. Thegas analyzer linearity requirement applies to physiological ranges ofuse, which typically are 50% to 80% of full-scale concentration for thetracer gas (e.g., CH₄ or He) and 30% to 50% of full-scale concentrationof CO gas, subject to variations in field operating conditions aspreviously described. Typically, linearity of gas analyzers is validatedand/or calibrated using several standard gases having differentconcentrations of the gas under test. Pre-mixed precision gas mixturessuitable for calibrating and/or validating gas analyzers with suitableaccuracy to meet the manufacturer's specifications and/or clinicalaccuracy requirements of the D_(LCO) parameter, are not, however,available and/or are extremely expensive.

Furthermore, reference standards (e.g., syringes) are generally unableto provide sufficiently accurate ratiometric gas concentrations toverify minimal gas analyzer linearity requirements, whether delivered bygas dilution methods or from methods utilizing multiple gas sources. Forexample, the mixing ratio of a dilution syringe can theoretically beindirectly determined by measuring relevant volumes of a dilutionsyringe with water and a suitable NIST traceable scale. However, theactual geometry and construction of dilution syringes can render such atheoretical approach unsatisfactory in practice. In particular, it canbe challenging or impossible to eliminate air pockets from within thesyringe, valve-less diffusion barriers have no defined boundary to watermeasure, and valve-based diffusion barriers may not be openable withoutdisassembly or modification. Because of the deficiencies of currentlyexisting standards and methods to calibrate and/or validate PFTinstruments to manufacturers' specifications and/or minimum clinicalstandards in a clinical environment, a need for improved methods anddevices for calibrating and/or validating PFT instruments is needed.Such improved methods and devices can be operable to produce PFTinstruments with improved accuracy and/or precision.

Some methods and apparatus described herein may be suitable to calibrateand/or validate PFT devices according to at least manufacturer'sspecifications and/or current minimum clinical standards/requirements.Methods and apparatus described herein may also be suitable to calibrateand/or validate PFT equipment to levels of accuracy and/or precisionbeyond current minimum clinical standards/requirements and/or may besuitable to calibrate and/or validate PFT equipment under variable fieldoperating conditions (including, for example, ambient temp changes of upto 15° C. and operator induced variability).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D depict a syringe in various configurations and a PFT device,according to an embodiment.

FIG. 2A is a schematic illustration of a syringe and a PFT device,according to an embodiment, and FIGS. 2B-2C are close-up illustrationsof a compliance feature of a syringe.

FIG. 3A is a schematic illustration of a syringe having a passive mixingfeature, according to an embodiment, and FIGS. 3B-3C are close-upillustrations of a passive mixing feature.

FIG. 4 is an illustration of an embodiment of a heat sink for a syringe.

FIG. 5 is a flow chart of a method of calibrating and/or validating aPFT device with a syringe, according to an embodiment.

FIG. 6 is a plot of concentrations produced by a syringe operatedaccording to the method of FIG. 5, according to an embodiment.

FIG. 7 is a flow chart of a method of calibrating and/or validating aPFT device with a syringe, according to an embodiment.

FIG. 8 is a plot of actual and measured concentrations produced by asyringe operated according to the method of FIG. 7, according to anembodiment.

FIG. 9 illustrates further details of the method of simultaneouslycalibrating and/or validating a syringe and a gas analyzer of FIG. 7.

FIG. 10 depicts a method of simultaneously calibrating and/or validatinga syringe and a gas analyzer using serial dilution and serialconcentration, according to an embodiment.

DETAILED DESCRIPTION

Some embodiments described herein relate to systems and methods forvalidating and/or calibrating volume measurements of PFT systems usingnon-pressurized ambient gas using flow technologies in a clinicalenvironment. Such systems and methods can use a syringe to provide aknown or standard volume of gas to a PFT instrument. Some existingsyringes used as gas volume standards are specified with a ±0.5%relative volume accuracy. This represents a quarter of the total errorallowanced for some flow sensors used for PFT tests that measure flowand/or volume. Although some existing syringes are theoreticallysuitable to deliver a volume of gas with ±0.5% accuracy under idealoperating conditions, in practice, achieving ±0.5% accuracy in terms ofgas volume requires the cylinder temperature to match ambient to within1° C. or less. The isothermal ideal gas law, PV=nRT, states that a gasvolume or pressure will change proportionally to its absolutetemperature. Any gas entering the syringe cylinder will expand orcontract if the temperature of the cylinder differs from the gastemperature. Under the most common use case, the body temperature of auser is approximately 10° C. higher than the temperature of the syringecylinder. Placing a hand on the cylinder during use or cradling thesyringe can heat the cylinder multiple degrees Celsius above ambientroom temperature. Because the gas entering the cylinder is at ambientroom temperature, differential of the same magnitude will exist betweenthe cylinder and the gas entering it. For example, a 3° C. differential,which may frequently occur during actual use, will introduceapproximately 1% error in the displaced gas volume due to expansion inaddition to the ±0.5% variations in volume discussed above.

Some embodiments described herein relate to reducing temperaturedifferentials between a syringe cylinder and ambient room air. This canbe achieved by increasing the thermal coupling of the cylinder with theroom air. For example, as discussed in further detail below withreference to FIG. 4, a syringe having a heat sink that can increase thesurface area of the syringe by at least three times, can provideimproved thermal coupling of the cylinder with the ambient room air. Asfurther discussed below, in some embodiments, heat sinks can have theadditional benefit of minimizing the possible contact surface area if ahand or other portion of an operator's body is placed on the syringe.

Some embodiments described herein relate a syringe that includes a heatsink such that the syringe cylinder has a surface area that is at leastthree times greater than that of a corresponding smooth cylinder. Someembodiments described herein also relate to moving a piston within asyringe having a heat sink such that the syringe draws a gas mixtureinto the syringe. The gas mixture can be held within the syringe for atleast five seconds, and the heat sink can maintain the temperature ofthe gas mixture within 1° C. of ambient temperature even if, forexample, the syringe is in contact with a body of the operator orexposed to sunlight. The piston can be moved within the syringe suchthat the gas mixture is expelled from the syringe into a pulmonaryfunction test device. The portion of the gas mixture expelled from thesyringe can be within 1° C. of ambient temperature such that the volumeper mole (specific volume) of gas mixture is substantially unchangedfrom when the gas mixture is drawn into the syringe to when the gasmixture is expelled from the syringe.

Some embodiments described herein relate to a method that includesdrawing ambient atmospheric gas having a room temperature into asyringe. The syringe can include a housing defining a primary surfacearea of the syringe, a piston, and a heat transfer element coupled tothe housing that has a surface area at least three times greater thanthe primary surface area of the syringe. The gas can be transferred fromthe syringe into a PFT device and the PFT device can be validated atleast in part on a measurement of a volume of gas transferred betweenthe PFT device and the syringe.

Some embodiments described herein relate to a system and method forperforming, validating, and/or calibrating volume measurements usingpressurized test gas (such as that used in D_(LCO) test and/or N₂washout lung volumes test using flow-based PFT systems). The syringe caninclude a compensator that can be a flexible mechanism that presents afluid dynamic compliance at or near the inlet of the test syringe. Themagnitude of the presented compliance may be at least 1 L atm′ whichcorresponds to the minimum typical physiologic compliance that an adulthuman would present to the D_(LCO) PFT testing equipment. As describedin further detail below with reference to FIGS. 2A-2C, a compensatoroperates by responding to pressure changes such that the volume itencloses changes proportionally to the pressure changes in that volume.It may be desirable for the compensator to have a high effectivebandwidth, because an uncompensated gas delivery device can oscillate atfrequencies on the order of 100 Hz. High bandwidth can be accomplishedby minimizing the mass of the compensator (e.g., thin construction) andby locating the compensator in close proximity to the syringe inlet,which can reduce inertial and resistive effects of the intervening gas.A viable compensator with a physiologic compliance value can beconstructed from silicon or other elastomeric rubber approximately 1 mmthick with a surface area on the order of 32 cm².

Some embodiments described herein relate to a syringe that includes asyringe body (also referred to as a housing), a piston disposed withinthe syringe body, and a compliance feature. The compliance feature canbe coupled to an outlet portion of the syringe body and can beconfigured to simulate compliance of a human respiratory system. Forexample, in some embodiments, the compliance feature can have acompliance greater than 1 L atm′ and/or less than 3 L atm′.

Some embodiments described herein relate to a method that includescoupling a syringe to a pulmonary function test device. The pulmonaryfunction test device can include a demand valve that is configuredand/or tuned to supply a test gas to a human subject when the humansubject inhales by matching an inhalation pressure with a supplypressure. The demand valve can have a dynamic behavior that is tuned toa human respiratory system. After coupling the syringe to the pulmonaryfunction test device, test gas can be drawn into the syringe, and thecompensator can simulate a human respiratory system such that the demandvalve operates within its design envelope and such that gas is drawninto the syringe at a substantially constant pressure at or nearatmospheric pressure. The test gas can subsequently be expelled from thesyringe into the pulmonary function test device.

Some embodiments described herein relate to a method that includescoupling a port of a syringe to a PFT device. The syringe can include ahousing, a piston, and a compensator such that the syringe has a fluiddynamic compliance of at least 1 L atm′. Gas can be transferred betweenthe PFT device and the syringe, and the PFT device can be validatedbased at least in part on a measurement of the gas transferred betweenthe pulmonary function test device and the syringe. For example, the PFTdevice can include a tank of pressurized gas and a demand valveconfigured to supply gas from the tank at or near atmospheric pressureto a human subject. The fluid dynamic compliance of the syringe cansimulate the fluid dynamic compliance of a human subject such that gasdelivered to the syringe via the demand valve is delivered atatmospheric pressure and/or within the design envelope of the demandvalve. Thus, the measurement of the gas can be performed on gasdelivered to the syringe within the design envelope of the demand valve.

Some embodiments described herein relate to a syringe that includes apiston moveably disposed within a housing. The piston and the housingcan collectively define a first working volume when the piston is in afirst position and a second working volume when the piston is in asecond position. The piston can be configured to discharge, though aport, gas having a volume equal to a difference between the firstworking volume and the second working volume when the piston is movedfrom the first position to the second position. The syringe can have afluid dynamic compliance of at least 1 L atm⁻¹.

Some embodiments described herein relate to a system that includes asyringe and a PFT device. The syringe can have a dynamic compliance ofat least 1 L atm⁻¹. The PFT device can include or be configured to becoupled to a pressurized source of a test gas. The PFT device can beconfigured to be coupled to the syringe such that the syringe can drawgas from the pressurized source. In some such embodiments, the PFTdevice can include a demand valve and the syringe can be configured tosimulate a human respiratory system such that the demand valve operateswithin its design envelope when the syringe draws gas from thepressurized source. The PFT device can include a volume sensorconfigured to measure a volume of gas moving between the PFT device andthe syringe and a gas analyzer configured to measure a concentration oftest gas expelled into the PFT device from the syringe.

Some embodiments described herein relate to a method that includesfilling a syringe with a test gas from a test gas source such that amixing volume of the syringe contains a first gas mixture having a firstconcentration of the test gas equal to a concentration of the test gassource. A portion of the first gas mixture can be expelled into a deviceconfigured to measure concentrations of the test gas (e.g., a pulmonaryfunction test device). A concentration of the test gas in the first gasmixture can be measured and/or recorded by the device in response toexpelling the portion of the first gas mixture into the device. Thesyringe can be filled with ambient air after expelling the portion ofthe first gas mixture such that the mixing volume of the syringecontains a second gas mixture having a second concentration of the testgas. A portion of the second gas mixture that has a volume equal to thevolume of the portion of first gas mixture can be expelled into thedevice. A concentration of the test gas in the second gas mixture can bemeasured and/or recorded by the device in response to expelling theportion of the second gas mixture. The syringe can be filled withambient air after expelling the portion of the second gas mixture suchthat the mixing volume of the syringe contains a third gas mixturehaving a third concentration of test gas. A portion of the third gasmixture having a volume equal to the volume of the portion of the secondgas mixture can be expelled into the device. A concentration of the testgas in the third gas mixture can be measured and/or recorded by thedevice in response to expelling the portion of the third gas mixtureinto the device. A decay rate coefficient can be determined based on themeasured concentration of the test gas in the first gas mixture, themeasured concentration of the test gas in the second gas mixture, andthe measured concentration of the test gas in the third gas mixture. Acorrection factor can be determined and/or applied to the device basedon the decay rate coefficient. The correction factor can offset at leastone of: (i) a deviation between the measured concentration of the testgas in the first gas mixture and the actual concentration of the testgas in the first gas mixture, (ii) a deviation between the measuredconcentration of the test gas in the second gas mixture and the actualconcentration of the test gas in the second gas mixture, or (iii) adeviation between the measured concentration of the test gas in thethird gas mixture and the actual concentration of the test gas in thethird gas mixture.

Some embodiments described herein relate to a method that includesserially diluting a test gas. Serially diluting a test gas can includeexpelling a portion of a first gas mixture having a first concentrationof a test gas from a mixing volume of a syringe into a device configuredto measure concentrations of the test gas (e.g., a pulmonary functiontest device). A concentration of the test gas in the first gas mixturecan be measured and/or recorded by the device in response to expellingthe portion of the first gas mixture into the device. The syringe can befilled with ambient air after expelling the portion of the first gasmixture such that the mixing volume of the syringe contains a second gasmixture having a second concentration of the test gas less than thefirst concentration of the test gas. A portion of the second gas havinga volume equal to the volume of the portion of first gas mixture can beexpelled into the device. A concentration of the test gas in the secondgas mixture can be measured and/or recorded by the device in response toexpelling the portion of the second gas mixture into the device. Thesyringe can be filled with ambient air after expelling the portion ofthe second gas mixture such that the mixing volume of the syringecontains a third gas mixture having a third concentration of test gasless than the second concentration of test gas. A portion of the thirdgas mixture having a volume equal to the volume of the portion of thesecond gas mixture can be expelled into the device. A concentration ofthe test gas in the third gas mixture can be measured and/or recorded bythe device in response to expelling the portion of the third gas mixtureinto the device. The measured concentration of the test gas in the firstgas mixture, the measured concentration of the test gas in the secondgas mixture, and the measured concentration of the test gas in the thirdgas mixture can collectively define a measured decay curve.

The method can further include serially concentrating a test gas.Serially concentrating the test gas can include filling a syringe from atest gas source that the mixing volume of the syringe contains a fourthgas mixture having a fourth concentration of the test gas. A portion ofthe fourth gas mixture can be expelled into the device. A concentrationof the test gas in the fourth mixture can be measured and/or recorded bythe device in response to expelling the portion of the fourth gasmixture into the device. The syringe can be filled from the test gassource after expelling the portion of the fourth gas mixture such thatthe mixing volume of the syringe contains a fifth gas mixture having afifth concentration of the test gas greater than the fourthconcentration of the test gas. A portion of the fifth gas mixture havinga volume equal to a volume of the portion of the fourth gas mixture canbe expelled into the device. A concentration of the test gas in thefifth gas mixture can be measured and/or recorded by the device inresponse to expelling the portion of the fifth gas mixture into thedevice. The syringe can be filled with test gas from the test gas sourceafter expelling the portion of the fifth gas mixture such that themixing volume of the syringe contains a sixth gas mixture having a sixthconcentration of the test gas greater than the fifth concentration ofthe test gas. A portion of the sixth gas mixture having a volume equalto the volume of the portion of the fifth gas mixture can be expelledinto the device. A concentration of the test gas in the sixth gasmixture can be measured and/or recorded by the device in response toexpelling the portion of the sixth gas mixture into the device. Themeasured concentration of the test gas in the fourth gas mixture, themeasured concentration of the test gas in the fifth gas mixture, and themeasured concentration of the test gas in the sixth gas mixturecollectively defining a measured growth curve.

The method can further include simultaneously characterizing (i) alinearity of the device, (ii) a dilution mixing ratio defined by themixing volume and the volume of the portion of the first gas mixture,and (iii) a growth mixing ratio defined by the mixing volume and thevolume of the portion of the fourth gas mixture. The device can bevalidated and/or calibrated based on the linearity of the device suchthat, when a seventh gas mixture is expelled into the device, the devicereports a concentration of test gas in the seventh gas mixtureconsistent with an actual concentration of test gas within the seventhgas mixture.

Some embodiments described herein relate to a method that includesfluidically coupling a syringe that is in a maximum volume configurationto a PFT device. The syringe can be moved from the maximum volumeconfiguration to a minimum volume configuration while the syringe isfluidically coupled to the pulmonary function test device such that afirst gas mixture is expelled from the syringe into the PFT device. Aconcentration of the test gas in the first gas mixture can be measuredusing a gas analyzer. The syringe can be moved from the minimum volumeconfiguration to the maximum volume configuration while the syringe isfluidically coupled to the pulmonary function test device such that thesyringe draws a displacement volume of the test gas from the pulmonaryfunction test device and such that the displacement volume less a systemvolume of the test gas mixes with a dead-space volume of the first gasmixture in the syringe to create a second gas mixture. The syringe canbe moved from the maximum volume configuration to the minimum volumeconfiguration while the syringe is fluidically coupled to the pulmonaryfunction test device such that the second gas mixture is expelled fromthe syringe into the PFT device. The concentration of the test gas inthe second gas mixture can be analyzed. The method can includeperforming any number of serial concentrations by mixing test gas with aprevious mixture of gas remaining in the dead-space of the syringeand/or measuring the concentration of the test gas in any of the serialconcentrations. As described in further detail herein, the mixing ratioof the syringe and the distortion function of the PFT device/gasanalyzer can be simultaneously determined based on the measuredconcentrations of test gas. The PFT device/gas analyzer can be validatedand/or calibrated based on the mixing ratio of the syringe and thedistortion function of the PFT device/gas analyzer.

Some embodiments described herein relate to a method that includesdetermining, based on a first signal received from a gas analyzer, afirst measured concentration of a test gas contained within a first gasmixture injected into a PFT device from a syringe that has a firstmixing ratio. A second measured concentration of the test gas containedwithin a second gas mixture that includes a portion of the first gasmixture diluted with atmospheric gas according the first mixing ratiocan be determined based on a second signal received from the gasanalyzer. A third measured concentration of the test gas containedwithin a third gas mixture that includes a portion of the second gasmixture diluted with atmospheric gas according the first mixing ratiocan be determined based on a third signal received from the gasanalyzer. A measured decay rate can be determined based on the firstmeasured concentration of the test gas, the second measuredconcentration of the test gas, and the third measured concentration ofthe test gas, and an eigenfunction over the measured decay rate can bedefined. A fourth measured concentration of the test gas containedwithin a fourth gas mixture injected into a PFT device from the syringecan be measured based on a fourth signal received from the gas analyzer.A fifth measured concentration of the test gas contained within a fifthgas mixture that includes a portion of the fourth gas mixtureconcentrated with the test gas according to a second mixing ratio can bedetermined based on a fifth signal received from the gas analyzer. Asixth measured concentration of the test gas contained within a sixthgas mixture that includes a portion of the fifth gas mixtureconcentrated with the test gas according to a second mixing ratio can bedetermined based on a sixth signal received from the gas analyzer. Ameasured concentration rate based on the fourth measured concentrationof the test gas, the fifth measured concentration of the test gas, andthe sixth measured concentration of the test gas can be determined, andan eigenfunction over the measured concentration rate can be defined.The eigenfunction over the measured decay rate and the eigenfunctionover the measured concentration rate can be simultaneously solved tosimultaneously determine the first mixing ratio, the second mixingratio, and a set of coefficients representing the non-linearity of thegas analyzer.

FIGS. 1A-1D depict schematic illustrations of syringe 100 in variousconfigurations and a PFT device 200, according to an embodiment. The PFTdevice 200 includes a gas analyzer 210, a volume sensor 220, a processor212, and memory 214. The syringe 100 is configured to draw and expel gasthrough the PFT device 200. Similarly stated, the syringe 100 isfluidically coupled to the PFT device 200.

The PFT device 200 includes an exhaust valve 232 and an intake valve234. In some embodiments, each of the exhaust valve 232 and the intakevalve 234 is or can be configured to be a one-way valve. The PFT devicecan be connected to a supply of test gas 236 via the intake valve 234.The supply of test gas 236 can be a pure test gas (e.g., carbonmonoxide, methane, etc.) suitable for detection by the gas analyzer 210or a gas mixture containing the test gas. As described in further detailherein, the concentration of the test gas in the supply of test gas 236may be unknown and/or the supply of test gas 236 can have an arbitraryconcentration.

The processor 212 and/or the memory 214 can be communicatively coupledto the gas analyzer 210 and/or the volume sensor 220 and operable toprocess signals received from the gas analyzer 210 and/or the volumesensor 220 and send and/or store a signal representing a concentrationof gas and/or measured volume. Similarly stated, the processor 212and/or the memory 214 can be operable to process raw signals from thegas analyzer 210 and/or the volume sensor 220 (or any other suitablesensors) and produce a calculated value. For example, the processor 212can be operable to integrate a signal associated with a linear and/orvolumetric flow rate from the volume sensor 220 to produce a measurementof volume. In some embodiments, the memory 214 can contain models,correlation coefficients, and/or other instructions that, when executedby the processor 212, cause the processor to calculate, report, and/orstore a measured value. Some embodiments described herein relate tocalibrating a PFT device. Calibrating a PFT device can include alteringmodels, calibration coefficients, and/or the like, stored in the memory214. Thus, some embodiments relate to altering or producing a PFT deviceusing the devices and methods described herein having calibrationcoefficients, models, or other suitable information stored in memorysuch that the PFT device performance is improved. In a clinicalenvironment, a PFT device calibrated using the methods and/or apparatusdescribed herein may be operable to measure volume, gas concentration,and/or physiologic parameters more accurately and/or with more precisionthan current existing PFT devices that have not been calibrated usingthe devices and/or methods described herein.

FIG. 1A shows the syringe 100 in a first configuration in which the PFTdevice 200 and the syringe include ambient gas (e.g., atmosphere). Forexample, the configuration shown in FIG. 1A can be the result from thePFT device 200 being flushed with ambient gas, for example, by thesyringe 100.

The syringe 100 includes a diffusion barrier 110, a piston 120, a firststop 130, and a second stop 140. The first stop 130 can be configured todefine a maximum volume of the syringe 100, while the second stop 140can be configured to define a minimum volume of the syringe 100. In someembodiments, the first stop 130 and/or the second stop 140 can bemoveable, such that the maximum and/or minimum volumes of the syringe100 are adjustable. As shown in FIG. 1A, the second stop 140 is disposedagainst a back portion 150 of the syringe 100 such that the syringe 100is in a minimum-volume configuration. In the minimum-volumeconfiguration, a dead space volume V_(dead) of the syringe 100 isdefined.

FIGS. 1B and 1C show the syringe 100 in a second configuration in whichthe first stop 130 is disposed against the back portion 150 of thesyringe 100 such that the syringe 100 is in a maximum-volumeconfiguration. The piston 120 can be moved from the first configurationshown in FIG. 1A to the second configuration shown in FIGS. 1B and 1C bydrawing it towards the back portion 150 of the syringe 100. Drawing thepiston 120 such that it moves towards the second configuration causesgas to be drawn from the supply of test gas 236 through the intake valve234 and the PFT device 200 and the diffusion barrier 110 into thesyringe 100. The diffusion barrier 110 allows gas flow when the piston120 is moving, but inhibits gas diffusion when the piston 120 isstationary. Thus, the PFT device 200 can be filled with gas from thesupply of test gas 236, and the diffusion barrier 110 inhibits gas fromentering or leaving the syringe 100 when the piston 120 is stationary.

The volume of gas drawn into the syringe 100 through the displacement ofthe piston 120 is referred to herein as the displaced volume V_(i) (alsoreferred to as the inspired volume). The sum of the displaced volumeV_(i) and the dead space volume V_(dead) is the mixing volume V_(mix) ofthe syringe 100. The volume of a gas channel of PFT device 200 and/orany volume between the intake valve 234 and the diffusion barrier 110 isa system volume V_(system). FIG. 1B schematically depicts the variousvolumes separately. FIG. 1C depicts a mixture of the displaced volumeV_(i) and the dead space volume V_(dead) in which the gas from thesupply of the test gas 236 is diluted by ambient air from the dead spacevolume V_(dead) and system volume V_(system).

FIG. 1D shows the syringe 100 in a third configuration in which thesecond stop 140 is disposed against the back portion 150 of the syringe100 such that the syringe 100 is in a minimum-volume configuration. Thepiston 120 can be moved from the second configuration shown in FIGS. 1Band 1C to the third configuration shown in FIG. 1D by pushing it awayfrom the back portion 150 of the syringe 100. Pushing the piston 120such that the syringe 100 moves towards the third configuration causesthe gas within the PFT device 200 to be expelled via the exhaust valve232 and the mixture of ambient air and gas from the supply of test gas236 shown in FIG. 1C to fill the PFT device 200. As described in furtherdetail herein, the piston 120 can be reciprocated any number of times.Each time the piston 120 moves towards the back portion 150 of thesyringe, the concentration of test gas in the syringe can increase.

The syringe 100 has a diluting behavior described by

$\begin{matrix}{A = \frac{V_{i} - V_{system}}{V_{mix}}} & (1) \\{M_{k} = {{AM_{src}} + {\left( {1 - A} \right)M_{k - 1}}}} & (2)\end{matrix}$

-   -   Where,    -   A is the mixing ratio of the syringe,    -   V_(i) is the displacement volume, shown and described above with        reference to FIG. 1B,    -   V_(system) is the system volume, shown and described above with        reference to FIG. 1B,    -   V_(mix) is the mixing volume, shown and described above with        reference to FIG. 1B,    -   M_(k) is the diluted, mixed concentration of the test gas in the        mixing volume V_(mix),    -   M_(src) is the concentration of the test gas in the test gas        source 236, and    -   M_(k-1) is the concentration of the test gas in the dead volume        \ideal and system volume V_(system) prior to drawing gas from        the test gas source 236, shown and described above with        reference to FIG. 1D.

FIG. 2A is a schematic illustration of a syringe 300 and a PFT device400, according to an embodiment. The syringe 300 and the PFT device 400can be structurally and/or functionally similar to the syringe 100 andthe PFT device 200 as shown and described above with reference to FIGS.1A-D. The syringe 300 includes a piston 320 operable to cause thesyringe 300 to draw gas from a test gas source 436 via the PFT device400 and an intake valve 434. The syringe 300 can be operable to draw gasto/from the PFT device 400, and the PFT device 200 (e.g., the volumesensor 210 and/or a gas analyzer 220) can be validated based at least inpart on a measurement of gas transferred between the PFT device 400 andthe syringe 300.

The test gas source 436 can be a pressurized gas source (e.g., a tankand/or a connection to a high-pressure test gas line) and the intakevalve 434 can be or include a demand valve and/or regulator operable toregulate the pressure of the test gas such that the PFT device 400receives the test gas at or near atmospheric pressure. The demand valvecan be configured to supply the test gas mixture when the human subjectinhales at atmospheric pressure by dynamically matching the pressure atwhich the test gas mixture is supplied to the inhalation pressure.

The intake valves (e.g., demand valves) of known PFT devices aretypically designed to supply gas based on the inhalation of a humansubject. Such intake valves may be conditionally stable, that is, theyare stable only within a finite envelope of operating conditions. Oneimportant parameter of that envelope is the dynamic characteristic ofthe “load” to which the regulator delivers gas. The “load” in this caseis a human being tested, which presents a fairly large dynamiccompliance to the regulator. In an adult human, the extra-thoracicstructure of the airways (e.g., mouth, nasal and larynx) is flexible andpresents a dynamic compliance in the range of 1-3 L atm⁻¹.

Existing devices used to validate and/or calibrate PFT equipment aretypically not operable to provide a dynamic load to the intake valvesthat is similar to a human being. For example, existing dilutionsyringes and the like typically have a compliance less thanapproximately one-tenth the compliance of a human being and therefore,if fluidically coupled to a PFT device, the intake valve may operateoutside its design envelope resulting in deviations from expected and/ordesigned gas delivery behavior. For example, gas may be delivered fromthe test gas source 436 at a higher or lower pressure than atmosphericor the delivered pressure may oscillate with a large amplitude,potentially disrupting any flow measurements.

The syringe 300 includes a compliance feature 330. The compliancefeature 330 can be an elastic structure such that the syringe 300 has acompliance similar to a human upper-respiratory system and such that thesyringe 300 presents a dynamic load to the PFT equipment 400 similar toa human being. Similarly stated, the syringe 300 including thecompliance feature 330 can have a dynamic compliance between 1 and 3 Latm⁻¹. In this way, the intake valve 434 can operate within its designenvelope and gas can be delivered from the test gas source 436 at ornear (e.g., within 5%) atmospheric pressure. Thus, the volume and/orconcentration of the gas drawn from the gas source 436 into the syringe300 can be well characterized and suitable for use validating and/orcalibrating the PFT device 400 for test modalities such as an N₂ washoutlung volumes test and/or a D_(LCO) test.

In some embodiments, the compliance feature 330 can include a conduitfor gas partially and/or completely constructed of an elastomericmaterial, such as silicon rubber or the like. In some embodiments, thecompliance feature can be constructed of silicon rubber having athickness between 0.25 mm and 4 mm and a surface area between 13 cm² and52 cm² (e.g., 1 mm thick and surface area of 32 cm²). For example, thecompliance feature 330 can be a cylindrical and/or other suitable hollowbody and/or passageway defining openings to atmosphere that are coveredby an elastomeric material. Similarly stated, the openings would be opento atmosphere but for the elastomeric covering. The compliance feature330 can be disposed on an end portion of the syringe 300 that isconfigured to be coupled to the PFT device 400 (e.g., opposite thepiston), which can reduce inertial effects of gas within the syringe 300that can reduce the effectiveness of compliance feature 330.

In addition or alternatively, the compliance feature 330 can be anelastomeric bellows-like structure, such as a structure that includesaccordion folds. Alternatively, the compliance feature 330 can be aservomechanism or other suitable electro-mechanical device coupled tothe piston 320 and configured to move the piston in response to changesin pressure to generate the fluid dynamic compliance.

The compliance feature 330 operates by responding to pressure changessuch that the volume enclosed by the compliance feature changesproportionally to pressure changes in that volume. The compliancefeature 330 can have a bandwidth suitable to simulate a humanrespiratory system to various demand valves and similar feedback controlmechanisms. Some existing demand valves can oscillate at frequencies onthe order of 100 Hz. Thus, the compliance feature 330 can be operable tosimulate a human respiratory system and/or dynamically stabilize ademand valve at frequencies of 100 Hz and higher. In some embodiments,the use of thin and/or low density materials for the construction of thecompliance feature 330 (e.g., a thin film) can provide a suitablylow-mass compliance feature 330 with a sufficiently high bandwidth tosimulate the human respiratory system.

An exemplary compliance feature 330 is shown in more detail in FIGS. 2Band 2C. As shown in FIGS. 2B and 2C, the compliance feature 330 is abellows-like structure constructed of silicon rubber and disposed on anend portion of a syringe.

FIG. 3A is a schematic illustration of a syringe 500 having a passivemixing feature 510 (also referred to herein as a fan or agitator),according to an embodiment. The syringe 500 can be structurally and/orfunctionally similar to the syringes 100 and/or 300 discussed above. Inparticular, the syringe 500 can be operable to calibrate and/or validatePFT equipment having a gas analyzer (not shown in FIG. 3). The syringe500 can be a dilution syringe operable to mix gas from a test gas sourcewith atmosphere or previous mixture. The passive mixing feature 510 canreduce wait times and/or improve mixing characteristics of the syringe500. In some embodiments the mixing feature 510 can be an undriven fanoperable to be mechanically energized by gas flowing into and/or out ofthe syringe. Similarly stated, the mixing feature can be operable tofreely spin or pinwheel when gas is drawn into the syringe. In someembodiments a nozzle or similar structure can cause relatively highvelocity gas to impinge upon the mixing feature 510. In otherembodiments, the mixing feature 510 can be operable to agitate gaseswithin the syringe 500 by any other suitable means, such as vibrationalagitation, creating vortices or other suitable turbulent flow patternswithin the syringe 500 and/or so forth. In some embodiments, the mixingfeature 510 can continue to agitate gas within the syringe 500 after thepiston has come to rest, for example, through inertial effects. Apassive mixing feature can be preferable to an active mixing featureand/or driven fan for simplicity of construction and to avoid heatingthe gas within the syringe, which as described in further detail hereincan produce inaccuracies when calibrating and/or validating a gas and/orvolume sensor of a PFT device.

In some instances, the syringe 500 can be operable to simulate aJones-Mead, single-breath D_(LCO) test. In a Jones-Mead, single-breathD_(LCO) test, the subject inhales a test gas, holds his or her breathfor approximately 10 seconds and then exhales. The passive mixingfeature 510 can be operable to cause an inspired test gas (e.g., V_(i))to completely mix with a dead volume of gas (e.g., V_(dead)) within 10seconds or less.

An exemplary mixing feature 510 is show in more detail in FIGS. 3B and3C.

FIG. 4 is an illustration of an embodiment of a heat sink 600 for asyringe, such as the syringes 100, 300, and/or 500 as described above.Existing devices and methods for validating and/or calibrating volumesensors of PFT devices (e.g., spirometers and the like) typicallyinvolve injecting a standard volume of gas from a syringe. To calibrateand/or validate a PFT device with sufficient accuracy to providephysiological representative and/or clinically meaningful data, syringesare typically accurate to ±0.5% of their mechanical displaced volume.Relatively large 3 L or 7 L syringes are common.

In use, an operator holds the syringe and reciprocates the plunger.Because of the size and weight of such syringes, it is common for theoperator to place a hand on the syringe body or cradle the syringe inhis or her arms. Such contact with the operator can cause thetemperature of the cylinder to rise appreciably above the ambient air,causing the temperature of any gas that enters the cylinder to also riseappreciably above ambient. A rise of the internal gas temperature of aslittle as 3° C. can introduce volumetric errors of 1% or greater,resulting in an inability to calibrate and/or validate a PFT device tomanufacturer specifications and/or clinical standards.

The heat sink 600 can increase the thermal conductivity between theambient atmosphere and the syringe cylinder, keeping the cylinder'stemperature closer to the temperature of the ambient air, which may varydue to exposure to HVAC and related variables, or when the cylinder isexposed to external heat sources such as the user or direct sunlight.The heat sink 600 will also decrease thermal conductivity between theuser and the syringe cylinder by reducing available surface area thatthe user may contact, thus reducing the amount of heat the user cantransfer to the cylinder during normal use. For example, the syringe canbe placed in thermal contact with a surface (e.g., a human body at 37°C.) at least 10° C. above room temperature (e.g., 23° C.) an elapsedtime of at least two minutes between drawing gas into the syringe andinjecting gas into a PFT device. During the elapsed two minutes, thespecific volume of gas within the syringe can change by less than 0.2%.In addition or alternatively, during the elapsed two minutes, thetemperature within the gas can change by less than 1° C. during theelapsed two minutes.

For example, the heat sink 600 can increase the surface area of theexterior wall of the syringe (also referred to herein as a primarysurface area) by at least three times. The heat sink 600 can therebyincrease the surface area of the syringe in contact with the atmosphereand the thin fins, as shown, can decrease the surface area available forcontact with the user. For example, a syringe can be characterized byits diameter d and length l, such that the surface area of the body ofthe syringe is π×d×l, excluding the end portions. With the heat sink600, the surface area of the body of the syringe can be at least threetimes π×d×l.

Such a syringe can be suitable for validating and/or calibrating a PFTdevice. For example, a syringe with the heat sink 600 can maintain atemperature of gas within the syringe within 1° C. of ambient when thesyringe is in close contact with a body of an operator for 10 seconds ormore. Similarly stated, even after being in contact with a body of anoperator for 10 seconds or more, the volume per mole of gas within thesyringe may remain substantially constant. Thus, the gas within thesyringe can be suitable for calibrating and/or validating a spirometeror other suitable volume sensor of a PFT device.

FIG. 5 is a flow chart of an embodiment of a method of calibratingand/or validating a PFT device with a syringe, such as the syringes 100,300, and/or 500 as shown and described above. For ease of reference,FIG. 5 is described with reference to FIGS. 1A-D. Optionally, at 710,the syringe 100 can be flushed and/or purged with ambient air such thatthe syringe 110 includes at most trace amounts of test gas. For example,the syringe 100 can be decoupled from the PFT device 200 and the pistonreciprocated a large number of times such that substantially no test gasis within the interior volume of the syringe. The piston of the syringe100 can then be drawn back such that the syringe is in a maximum-volumeconfiguration and the syringe coupled to the PFT device 200.

At 720, the piston 120 can be moved into a minimum-volume configuration,such as shown in FIG. 1A. In an instance where the syringe 100 waspreviously flushed with atmosphere, the PFT device 200 can be filledwith atmosphere (e.g., as shown in FIG. 1A). The gas analyzer 210 canmeasure a concentration of test gas in the atmosphere. In some instancesthe test gas is present only in trace amounts (e.g., 2,500 ppb or less)in the atmosphere and/or the concentration of the test gas in theatmosphere can be below a detection limit of the gas analyzer, such thatthe gas analyzer 210 reports (or is configured to report) zero test gas.

At 730, the piston 120 can be moved from a minimum-volume configuration,into the maximum-volume configuration. The piston can draw the displacedvolume V_(i) of the test gas mixture from the test gas source 236through the PFT device 200 and into the syringe. The quantity of thetest gas mixture drawn into the syringe (the displacement volume V_(i)less the system volume V_(system)) can mix with the gas disposed withinthe dead volume V_(dead) and system volume V_(system), as shown, forexample, in FIGS. 1B and 1C.

After the piston 120 is moved into the maximum-volume configuration, at730, the process can be repeated any number of times. Each time thesyringe moves into the minimum-volume configuration, at 720, a mixtureof test gas and atmosphere can be injected into the PFT device 200, andthe concentration of test gas can be measured by the gas analyzer 210.Then, each time the syringe moves into the maximum-volume configuration,at 730, gas drawn from the test gas source 236 can mix with the gas inthe dead volume V_(dead) and system volume V_(system) from the previousminimum-volume configuration.

For example, as shown in FIG. 1D, the piston 120 is moved into theminimum-volume configuration, expelling a mixture of atmosphere and thetest gas mixture into the PFT device 200. A concentration of test gas inthis mixture can be detected by the gas analyzer 210. Subsequently, themixture shown in FIG. 1D can be mixed with additional test gas mixture,further concentrating the gas mixture shown in FIG. 1D. This mixture canbe expelled into the PFT device 200 and concentration of the test gas inthis mixture can again be measured by the gas analyzer 210. In this way,a series of serial concentrations of the test gas can be measured. FIG.6 is a plot of concentration produced by a syringe operated according tothe method of FIG. 5, in an embodiment in which the test gas source 236contains pure test gas, the atmosphere contains no test gas, and themixing ratio A is 0.5. As shown in FIG. 6 the concentration of test gasin the syringe approaches the concentration of the test gas mixtureasymptotically according to the following formula.

M _(k) =M _(src)(1−A ^(k))  (3)

-   -   Where,    -   A is the mixing ratio of the syringe,    -   M is a concentration of test gas and M_(src) is a concentration        of test gas in the test gas source, and    -   k is a cycle index such that M_(k) is the diluted, mixed        concentration of the test gas in the mixing volume V_(mix) after        k cycles of the piston.

Gas analyzers used in most commercially available PFT devices typicallyrely on optical absorption using, for example, non-dispersive infrared(NDIR) analyzers, to measure test gas concentration. According to theBeer-Lambert law, absorption has a linear relationship with gasconcentration. NDIR analyzers, however, measure optical absorbanceindirectly, relying on the effect that absorption has on detected lightintensity and are therefore fundamentally nonlinear. The relationshipbetween absorption and the intensity of light entering and leaving theanalyzer's sample chamber is:

I _(m) =I ₀ e ^(−A)  (4)

-   -   Where,    -   A is the absorbance,    -   I₀ is the light intensity entering the sample chamber, and

-   I_(m) is the light intensity leaving the chamber.

In addition, practical NDIR implementations introduce additional secondorder nonlinear behaviors beyond those expressed in equation (4).Furthermore, sensor nonlinearity varies significantly from device todevice due to production variability. Accordingly, to provide usefuldata, a gas analyzer must be calibrated and/or validated. Data generatedfrom gas analyzers (e.g., NDIR analyzers) may also be post-processedand/or linearized to produce a linear representation of the measured gasconcentration. Coefficients associated with the linearization processcan be obtained by calibrating the analyzer using multipleconcentrations of one or more test gases. As discussed above, tovalidate and/or calibrate a PFT device to manufacturerspecifications/clinical requirements and/or to provide physiologicallyrepresentative/clinically meaningful data, it is desirable for thenonlinearity of gas analyzers to be on the order of 0.5% relative tofull scale. Bottled gas references with sufficiently accurateconcentrations and range to characterize an analyzer to the accuracylevels required by manufacturer and/or clinical standards are notreadily available and/or are extremely expensive. Even if suitablebottled gas mixtures can be created, such standard mixtures aregenerally unsuitable and/or unavailable for use in the field (e.g.,outside the equipment maker's manufacturing facilities).

As a result, rather than using multiple bottled gas references, variousdilutions and/or concentrations of a single mixture of test gas can bemade using a syringe or similar device, such as the syringes 100, 300,500 described above. If the nonlinearity of gas analyzers less than±0.76% relative to full scale is to be verified with a 95% probability,the combined standard deviation of the dilution syringe and the analyzerbeing verified should be less than 0.38% relative to full scale. Thisimplies that the dilution syringe should generate gas concentrationratio values with a standard deviation on the order of 0.1% relative tofull scale, which can be difficult or impossible to achieve by usingcommercially available gas mixtures.

Some embodiments described herein relate to linearizing, calibratingand/or validating a gas analyzer ratiometrically, rather than relyingupon the accuracy of individual gas mixture concentrations. Similarlystated, because existing gas mixing and/or dilution techniques aregenerally unsuitable for providing a known concentration of a test gaswith sufficient accuracy, some embodiments described herein relate to asyringe that, rather than providing highly accurate mixing volumes,produces highly precise and highly repeatable mixing volumes. Forexample, although the absolute mixing volumes of the syringe shown inFIGS. 1A-1D may not be known with a high degree of accuracy, when thesyringe is cycled according to the method described with reference toFIG. 5, each movement of the piston replicates the same volume with ahigh degree of precision. Accordingly, the syringe will concentrate thetest gas according to equation (3) with little deviation (e.g., lessthan 0.1% deviation from full scale).

FIG. 7 is a flow chart illustrating details of simultaneouslycalibrating and/or validating a syringe and a gas analyzer, according toan embodiment. As discussed above, current art with respect tocalibrating or validating a gas analyzer rely on applying a standardwith an accurately known concentration of a test gas. As also discussedabove, it can be difficult or impossible to produce sufficientlyaccurate mixtures of the test gas. Rather than apply a standard gasmixture to the gas analyzer, the method of FIG. 7 simultaneouslyvalidates and/or calibrates the syringe and the gas analyzer, withoutrelying on a standard concentration of test gas. The method of FIG. 7 ispartially an exponential complement of the method shown and describedwith reference to FIGS. 5 and 6. FIGS. 5 and 6 describe an exponentialserial concentration of test gas using a syringe. FIG. 7 describes anexponential serial dilution of test gas.

At 810, optionally, the syringe 100 can be flushed and/or purged withgas from test gas source 236 such that the syringe 100 includes at mosttrace amounts of atmospheric gas. For example, the state of the syringeat 810 can be achieved by performing the method of FIG. 5 a large numberof times such that the mixing volume V_(mix) of the syringe includes amixture of gas having a concentration of test gas approaching theconcentration of test gas in the test gas source 236.

At 820, the syringe 100 can be moved into a minimum-volume configurationexpelling the displaced volume V_(i) into the PFT device 200, and thegas analyzer 210 can measure a concentration of test gas in the mixture.Then, at 830, the syringe 100 can be moved from a minimum-volumeconfiguration, into the maximum-volume configuration. The piston 120 candraw the displaced volume V_(i) of the atmosphere into the syringe 100.For example, the test gas source 236 can be decoupled from the PFTdevice, the intake valve 234 can be moved into a configuration in whichit draws atmosphere rather than gas from the test gas source, and/or theexhaust valve 232 can be reversed such that it functions as an intakevalve. The quantity of the atmosphere drawn into the syringe 100 (thedisplacement volume V_(i) less the system volume V_(system)) can mixwith the gas disposed within the dead volume V_(dead) and system volumeV_(system).

After the syringe 100 is moved into the maximum-volume configuration, at830, the process can be repeated any number of times. Each time thesyringe 100 moves into the minimum-volume configuration, at 820, amixture of test gas and atmosphere can be injected into the PFT device200, and the concentration of test gas can be measured. Then, each timethe syringe moves into the maximum-volume configuration, at 830,atmosphere can be drawn into the syringe and mix with the gas remainingin the dead volume V_(dead) and system volume V_(system) from theprevious minimum-volume configuration. In this way a series of serialdilutions of the test gas can be measured.

FIG. 8 is a plot showing the theoretical actual concentration of testgas delivered by a syringe operated according to the method of FIG. 7,in an embodiment in which the syringe is initially flushed with 100%test gas, the atmosphere contains no test gas, and the mixing ratio A is0.5. FIG. 8 further shows a simulation of a measured concentration ofthe concentration of the test gas according to a PFT device. As shown inFIG. 8 the concentration of test gas in the syringe approaches zero (ormore accurately, the concentration of test gas in the atmosphere)asymptotically according to the following formula.

M _(k) =M _(src) A ^(k)  (5)

-   -   Where,    -   A is the mixing ratio of the syringe,    -   M is a concentration of test gas and M_(src) is a concentration        of test gas in the test gas source, and    -   k is an cycle index such that M_(k) is a the concentration of        the test gas in the mixing volume V_(mix) after k cycles of the        piston.

Notably, equation (5) (and equation (3) described above) are independentof any individual measurement of the concentration of the test gas andof all parameters of the dilution syringe other than mixing ratio A.Methods described herein effectively result in the syringe and the PFTdevice simultaneously being characterized, calibrated, and/or validatedbased on first principles, rather than by reference to a standard.

As shown in FIG. 8, the gas analyzer 210 can produce the distorted“measured” representation of the “actual” concentration of the gas dueto noise, nonlinearity, scalar errors, time dependencies, and/or anyother source of measurement error. Such measurement errors can bemodeled and/or extracted based on the known exponential behavior of aserial dilution.

FIG. 9 illustrates further details of the method of simultaneouslycalibrating and/or validating a syringe and a gas analyzer, shown anddescribed with reference to FIG. 7. Ultimately a predictor module canproduce a representation of the dilution process M_(P) _(k) .

The syringe (referred to herein as the “apparatus” with reference toFIGS. 9 and 10) produces a physical series of concentrations M_(k)according to mixing ratio A of the apparatus. The PFT device and/or gasanalyzer (referred to herein as the “instrument” with reference to FIGS.9 and 10) can return a distorted representation of the series ofconcentrations V_(k). The instrument and linearizer module can berepresented by a single function ƒ_(Proc) representing the gas analyzer,which converts physical concentrations M_(k) into representative valuesM_(s).

The linearizer module and an optimizer module can parameterize andresolve the decay rate A_(P) of the syringe. Similarly stated, althoughthe exponential behavior of the apparatus is known, the decay rate A_(P)itself may not be known with sufficient accuracy, and can be resolved bythe linearizer and optimizer modules. To resolve the decay rate A_(P),the linearizer module and/or the optimizer module can use the distortedrepresentation of the series of concentrations V_(k) as a reference toresolve a set of coefficients C that result in the linearizer moduleproducing a set of exponentially related values M_(S) _(k) . Similarlystated, the coefficients C effectively linearize ƒ_(Proc). Thus, thelinearizer function ƒ_(Lin) is the inverse of the instrument functionƒ_(Inst).

The exponentially related values M_(S) _(k) produced by the linearizermay have a decay rate different from the decay rate physically producedby the apparatus M_(k), but contain decay rate information from theapparatus and can provide a decay rate reference for the optimizationmodule. The optimization module can search for a set of coefficients Cand a predicted decay rate parameter A_(P) that minimize the leastsquare difference between the set of exponentially related values M_(S)_(k) and the set of values representing the dilution process M_(P) _(k). The optimization module can employ any suitable search algorithm toproduce the set of coefficients C using any suitable regressionanalysis. As M_(S) _(k) converges to M_(P) _(k) the linearized valuesM_(S) will be as exponentially related as the linearization functionƒ_(Lin) will allow, and the decay rate parameter A_(P) produced by thepredictor module will match the decay rate of M_(S), in a least squaresense. Thus, the predictor module can produce the exponentially relatedreference for the coefficient C search and the linearizer module canproduce the decay rate reference for the predictor module's parametersearch. It should be noted that the coefficients C and decay rateparameter A_(P) are solved simultaneously, not in an alternating manner.As the optimizer module iterates, the measured values M_(S) become moreexponentially related and the decay rate of the predicted value M_(P)converges to a fixed value.

Concisely, the optimization process calculates N number of coefficientsC and predicted decay rate A_(P) according to the following:

$\begin{matrix}{{\lim\limits_{N\rightarrow\infty}{f_{Proc}\left( {M_{k},C_{1},{C_{2}\ \cdots\mspace{14mu} C_{N}}} \right)}} = {M_{S_{k}} = {M_{P_{k}} = {A_{P}^{k} = \left( {\lambda A} \right)^{k}}}}} & (6)\end{matrix}$

According to equation (6), ƒ_(Proc) is an eigenfunction over A of theapparatus's function A^(k). If ƒ_(Proc) is a set of exponential valuesof decay rate A, ƒ_(Proc) will return a set of exponential values, butwith a decay rate of A scaled by λ. Thus, the optimization module caninclude or be operable to execute an eigenfunction solver that solvesfor the nearest eigenfunction that satisfies equation (6).

In the instance where the optimization module returns a set ofcoefficients C that make ƒ_(Proc) linear, then λ=1 and A_(P)=A. In suchan instance, the mixing coefficient A of the apparatus and the inverseof the instrument's distortion ƒ_(Inst) are also known or solved,resulting in both the apparatus and the instrument being fullycharacterized. It should be noted, however, that in the process shown inFIG. 9 there exists an infinite number of possible eigen functions forA^(k). Similarly stated, there exist an infinite number of possiblenonlinearities of ƒ_(Proc) that satisfy equation (6) and therefore, theoptimizer module is not fully constrained.

FIGS. 7-9 and equation (6) have thus far been described with referenceto serial dilution. Equation (6), can be fully constrained byconsidering serial concentration, as described with reference to FIGS. 5and 6 in addition to serial dilution as described with reference toFIGS. 7 and 8. Similarly stated, the apparatus has the capability toperform two separable mixing modes, serial dilution and serialconcentration, characterized by two separable models, 1−A^(k)(concentration) and its complement A^(k) (dilution). In some instances,the mixing ratio, A can also be independent for concentration anddilution (e.g., the first stop 130 and/or the second stop 140 can bemoved between a dilution phase and a concentration phase), such that themodels can be expressed as A_(D) ^(k) for dilution and 1−A_(U) ^(k) forconcentration.

FIG. 10 is similar to FIG. 9, but depicts a process in which a predictormodule can produce a representation of the dilution and/or concentrationprocess M_(P) _(k) based on both a serial dilution, noted by thesubscript D (e.g., A_(D) ^(k)) and serial concentration, noted by thesubscript U (e.g., A_(U) ^(k)). The method depicted in FIG. 10 canproduce a single set of linearization coefficients C for both theconcentration and dilution modes. As a result, the process will convergeon a set of linearization coefficients C such that ƒ_(Proc) converges tothe nearest eigenfunction of both mixing modes. The only eigenfunctionthat exists for both mixing models is the function M_(S)=M_(k), thelinear case.

ƒ_(Proc) will always converge in the fully constrained algorithm to alinear function. It follows that ƒ_(Proc) with coefficients C willconverge to the inverse of the instrument function ƒ_(Inst), whichintroduced distortion into the values V. If ƒ_(Proc) is linear, then bydefinition the decay rates in M_(s) match the physical decay rates of M.Consequently, the optimizer module will force the predictor module'sparameters A_(D) _(P) and A_(U) _(P) to converge to the physical decayrates A_(D) and A_(U), respectively, which are the mixing ratios of theapparatus. These physical mixing ratios are the attributes that theprocess is intended to determine.

The fully constrained optimization process calculates N number ofcoefficients C and both predicted decay rates A_(D) _(P) and A_(U) _(P)according to the following:

$\begin{matrix}{{\lim\limits_{N\rightarrow\infty}\left| \begin{matrix}{{f_{Proc}\left( {\left\{ {M_{D_{k}},M_{U_{k}}} \right\},C_{1},{C_{2}\ \cdots\mspace{14mu} C_{N}}} \right)} = \left\{ {A_{D}^{k},{1 - A_{U}^{k}}} \right\}} \\{{and},\mspace{11mu}{\forall{{M0} < M < 1}}} \\{{A_{D_{P}} = A_{D}},{A_{U_{P}} = A_{U}}}\end{matrix} \right.}\;} & (7)\end{matrix}$

Applying equation (7), not only are the mixing ratios of the apparatusdetermined, but also the nonlinearity of the instrument is determinedvia the linearization function ƒ_(Lin) and its associated coefficientsC. Both the apparatus and instrument are characterized by this process.

It should be understood that where methods and equations describeexponential operations having the form M=A^(k), one skilled in the artwould understand that such methods and equations can be configured toprocess the recursive definition of the exponential (e.g., M_(k)=AM_(k-1)), such as is shown and described above with reference toequation (2). In some instances, methods and equations described herein,altered to process the recursive definition of exponentials caneliminate constraints related to, for example, the order in which serialdilution and serial concentration are performed. One skilled in the artwould understand that such equations would otherwise produce the sameresults and can be proven by similar analysis as described in furtherdetail below.

The method shown and described with reference to FIG. 10 can bemathematically proven as follows. According to equations (6) and (7),only one eigenfunction exists for both mixing functions A_(D) ^(k) and1−A_(U) ^(k). Restated, the eigenfunction spaces of A_(D) ^(k) and1−A_(U) ^(k) intersect at one singular point: ƒ: x→x, the linear case.(The linear function ƒ: x→x (or ƒ: x→λx) is an eigenfunction of anyfunction.) The method depicted in FIG. 9 includes solving for a set ofcoefficients C such that ƒ_(Proc) is an eigenfunction of A_(D) andA_(U), according to equation (7). Moreover, the method depicted in FIG.9 allows for the eigenfunction of A_(D) and A_(U) to be solved over anymixing coefficient(s) presented by the apparatus. The eigenfunctions ofboth mixing models A_(D) ^(k) and 1−A_(U) ^(k). can be described as:

(A _(D) ^(k) ,M)=(λ_(D) A _(D))^(k) =A _(D) ^(k)+ƒ(M)  (8)

(1−A _(U) ^(k) ,M)=1−(λ_(U) A _(U))^(k)=1−A _(U) ^(k)+ƒ(M)  (9)

Solving for ƒ(M) gives:

ƒ(M)=(λ_(D) A _(D))^(k) −A _(D) ^(k)  (10)

ƒ(M)=A _(U) ^(k)−(λ_(U) A _(U))^(k)  (11)

Equations (10) and (11) can be equated to the same function ƒ(M) becauseboth mixing models (concentration and dilution) are operated on by onlyone function ƒ_(Proc), which occurs in the M, or concentration, domainas shown in FIG. 9. Applying equations (2) and (3), M=A_(D) ^(k) andM=1−A_(U) ^(k), equations (10) and (11) can be transformed from the kdomain into the M domain:

$\begin{matrix}{{f(M)} = {M^{\frac{\ln{({\lambda_{D}A_{D}})}}{\ln{(A_{D})}}} - M}} & (12) \\{{f(M)} = {1 - M - \left( {1 - M} \right)^{\frac{\ln{({\lambda_{U}A_{U}})}}{\ln{(A_{U})}}}}} & (13)\end{matrix}$

Equating equations (12) and (13) in the M domain gives:

$\begin{matrix}{M^{\frac{\ln{({\lambda_{D}A_{D}})}}{\ln{(A_{D})}}} = {1 - \left( {1 - M} \right)^{\frac{\ln{({\lambda_{U}A_{U}})}}{\ln{(A_{U})}}}}} & (14)\end{matrix}$

Equation (14) defines the intersection of the eigenfunction spaces overA of A_(D) ^(k) and 1−A_(U) ^(k). It follows from equations (6) and (7),that λ_(D)=1 and λ_(U)=1 satisfy equation (14). The solution to thesystem of equations (15) shows that λ_(D)=1 and λ_(U)=1 is the onlypossible solution that satisfies equations (14), which proves theassertion of equation (7).

$\begin{matrix}{{M^{\frac{\ln{({\lambda_{D}A_{D}})}}{\ln{(A_{D})}}} = {1 - \left( {1 - M} \right)^{\frac{\ln{({\lambda_{U}A_{U}})}}{\ln{(A_{U})}}}}}{{\frac{d}{dM}\left( M^{\frac{\ln{({\lambda_{D}A_{D}})}}{\ln{(A_{D})}}} \right)} = {\frac{d}{dM}\left( {1 - \left( {1 - M} \right)^{\frac{\ln{({\lambda_{U}A_{U}})}}{\ln{(A_{U})}}}} \right)}}{{\frac{d^{2}}{dM^{2}}\left( M^{\frac{\ln{({\lambda_{D}A_{D}})}}{\ln{(A_{D})}}} \right)} = {\frac{d^{2}}{dM^{2}}\left( {1 - \left( {1 - M} \right)^{\frac{\ln{({\lambda_{U}A_{U}})}}{\ln{(A_{U})}}}} \right)}}{{\frac{d^{3}}{dM^{3}}\left( M^{\frac{\ln{({\lambda_{D}A_{D}})}}{\ln{(A_{D})}}} \right)} = {\frac{d^{3}}{dM^{3}}\left( {1 - \left( {1 - M} \right)^{\frac{\ln{({\lambda_{U}A_{U}})}}{\ln{(A_{U})}}}} \right)}}} & (15)\end{matrix}$

Equation (16) represents the solution to the system of equations (15),following a significant amount of algebraic manipulation due to thethird order nature of the problem.

$\begin{matrix}{\left\{ {\lambda_{D},\lambda_{U},A_{D},A_{U}} \right\} = \left\{ \begin{matrix}{{\lambda_{D} = 1},{\lambda_{U} = 1},{A_{D} \neq 1},{A_{U} \neq 1},{\forall M},{{M \neq 0} ⩓ {M \neq 1}}} \\{{\lambda_{D} \in},{\lambda_{U} \in},{A_{D} \neq 1},{A_{U} \neq 1},{M = {{0 ⩔ M} = 1}}}\end{matrix} \right.} & (16)\end{matrix}$

Equation (16) constrains the domain of equation (7) to 0<M<1, themaximum normalized range of the measurement. Accordingly, λ_(D)=1 andλ_(U)=1 is the only solution that satisfies equation (7).

Returning to FIGS. 5, 7, 9, and 10, it should be understood that serialdilutions and/or concentrations of a test gas can be expelled from asyringe (e.g., the syringe 100) into a PFT device to validate,calibrate, and/or linearize the PFT device 200. Thus, each time thesyringe is moved into a minimum-volume configuration, the PFT device 200can produce and/or record a measured concentration of the gas expelledinto the PFT device. A minimum of three serial concentrations and/orthree serial dilutions can be used to characterize the linearity of thePFT device 200 and/or produce the representation of theconcentration/dilution process M_(P) _(k) as described above. Similarlystated, the methods described with reference to FIGS. 5, 7, 9, and 10can allow for a dilution mixing ratio, a concentration mixing ratioand/or device linearity, to be determined based on the measuredconcentrations of the test gas. In some embodiments, the PFT device 200can be calibrated by calculating and/or applying a correction factor tothe PFT device (e.g., adjusting an offset, gain, and/or linearity of thePFT device) based on deviations between measured concentrations andpredicted concentrations M_(P) _(k) . In other embodiments, the PFTdevice 200 can be validated and/or fail validation based on a comparisonbetween measured concentrations and predicted concentrations. Forexample, after calibration and/or to validate a PFT device, one or allmeasured concentrations of the test gas and/or measured concentrationsof subsequent mixtures of test gas applied to the PFT device may bewithin 0.5% of actual and/or predicted concentrations.

Traditionally, PFT equipment is calibrated at the time of manufactureand validated in the field. Due to the expense and unavailability ofprecision gas mixtures, it has generally not been possible to accuratelyvalidate, let alone calibrate, PFT equipment in the field. Furthermore,traditionally there has been large device-to-device variability ofdeployed PFT equipment, suggesting that accurate calibration of PFTequipment has not previously been possible at all. Unlike existingdevices and/or methods purporting to calibrate and/or validate PFTequipment using precision gas mixtures and/or “standardized” dilutionsof a gas mixture, the methods and apparatus described herein do not relyon precision mixtures of gas, or even devices able to produce anaccurate mixing ratio. Rather, the methods and apparatus describedherein are able to accurately validate and/or calibrate PFT equipment attime of manufacture and/or in the field with a single test gas sourcecontaining an arbitrary mixture of test gas and a syringe suitable toconsistently draw the same volume. Similarly stated, methods andapparatus described herein are suitable to calibrate and/or validate PFTequipment by precisely and repeatedly producing the same volumetricdisplacement, rather than producing an absolutely accurate volumetricdisplacement. Accordingly, the apparatus and methods described hereinare generally suitable for use on a wide range of PFT equipment, can beused to validate and/or calibrate PFT equipment such that the PFTequipment can confidently produce accurate physiologic data and canreduce or eliminate device-to-device variability.

Furthermore, the PFT device can be operable to identify testingirregularities and/or instrument irregularities. For example, industrystandard criteria (e.g., exhalation length, exhalation volume,exhalation pattern, etc.) can be used to determine whetherirregularities in a PFT are the likely result of patient and/ortechnician error. Additionally, the PFT device can detect instrumentirregularities when, for example, the PFT device has not been recently(within predetermined period of time) calibrated/validated, when PFTresults are consistent with a properly performed test, when PFTirregularities are consistent with a calibration error, etc. When aninstrument irregularity is detected, an alert can be generated toinstruct a technician to correct an error with an instrument and/or toprevent the technician from performing tests with the PFT device. Forexample, when an instrument irregularity is detected, the technician canbe instructed to calibrate the PFT device, perform maintenance on thePFT device, initiate a service call, or take any other suitable action.When a testing irregularity is detected, the technician can beinstructed to ask the patient to re-perform the test, alternate acoaching instruction for the patient (e.g., instruct the patient toexhale slower, faster, more forcefully, etc.), attend remedial training,that the patient is too ill to perform the PFT, or take any othersuitable action.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, notlimitation, and various changes in form and details may be made. Forexample, although some embodiments describe PFT devices, in someinstances, the syringes and/or methods described herein are suitable tovalidate and/or calibrate other devices that measure gas concentration.As another example, some embodiments describe PFT devices with gasanalyzers and/or volume sensors. It should be understood, however, thatunless the context clearly dictates otherwise, some embodiments of PFTdevices may not include one or more described components (e.g., a volumesensor). As yet another example, some embodiments describe a syringewith a compliance feature. It should be understood that compliancefeatures described herein can be integral to a syringe and/or removeablycoupled to a syringe. For example, a compliant adapter configured to beremoveably coupled to a PFT device and a syringe such that theadapter-syringe system has a compliance similar to that of a humansubject should be understood as a syringe including an adapter.

Where methods described above indicate certain events occurring incertain order, the ordering of certain events may be modified.Additionally, certain of the events may be performed concurrently in aparallel process when possible, as well as performed sequentially asdescribed above. It should further be understood that methods describedherein may be partially and/or entirely computer implemented. Similarlystated, where events of methods are described herein, it should beunderstood that these events may be carried out, performed, and/orcaused to be performed by a processor executing non-transitory code. Anyportion of the apparatus and/or methods described herein may be combinedin any combination, except mutually exclusive combinations. Theembodiments described herein can include various combinations and/orsub-combinations of the functions, components and/or features of thedifferent embodiments described.

Some embodiments described herein relate to calibrating and/orvalidating PFT equipment. Some such embodiments can further includerecording, storing, and/or reporting PFT characterization and/orcalibration result measurements. Such embodiments can further includesuitable equipment (e.g., computers, servers, internet access, intranetaccess, cloud access, etc.) for recording, storing, and/or reportingsuch information. Such embodiments can also be operable to store and/orreport PFT device specifications and/or physiologic testing capabilities(e.g., spirometry, nitrogen washout, D_(LCO), plethysmography, etc.) andbe operable to alert the operator in the event that the PFT equipmentdoes not include a valid verification prior to testing patients (e.g.,if the PFT equipment is out of calibration, has an expiredcalibration/validation, and/or the PFT equipment is not capable ofmeasuring a patient with clinically meaningful accuracy and/orprecision).

Some embodiments described herein refer and/or relate to modules. Amodule can be or include hardware and/or software (e.g., stored inmemory or executing on a processor) operable to perform the referencedfunctions.

Some embodiments described herein, such as embodiments referring orrelating to modules can relate to a computer storage product with anon-transitory computer-readable medium (also can be referred to as anon-transitory processor-readable medium) having instructions orcomputer code thereon for performing various computer-implementedoperations. The computer-readable medium (or processor-readable medium)is non-transitory in the sense that it does not include transitorypropagating signals per se (e.g., a propagating electromagnetic wavecarrying information on a transmission medium such as space or a cable).The media and computer code (also can be referred to as code) may bethose designed and constructed for the specific purpose or purposes.Examples of non-transitory computer-readable media include, but are notlimited to: magnetic storage media such as hard disks, floppy disks, andmagnetic tape; optical storage media such as Compact Disc/Digital VideoDiscs (CD/DVDs), Compact Disc-Read Only Memories (CD-ROMs), andholographic devices; magneto-optical storage media such as opticaldisks; carrier wave signal processing modules; and hardware devices thatare specially configured to store and execute program code, such asApplication-Specific Integrated Circuits (ASICs), Programmable LogicDevices (PLDs), Read-Only Memory (ROM) and Random-Access Memory (RAM)devices. Other embodiments described herein relate to a computer programproduct, which can include, for example, the instructions and/orcomputer code discussed herein.

Examples of computer code include, but are not limited to, micro-code ormicro-instructions, machine instructions, such as produced by acompiler, code used to produce a web service, and files containinghigher-level instructions that are executed by a computer using aninterpreter. For example, embodiments may be implemented using Java,C++, or other programming languages (e.g., object-oriented programminglanguages) and development tools. Additional examples of computer codeinclude, but are not limited to, control signals, encrypted code, andcompressed code.

What is claimed is:
 1. A method, comprising: drawing ambient atmosphericgas having a room temperature into a syringe having a housing defining aprimary surface area of the syringe, a piston, and a heat transferelement coupled to the housing and having a surface area at least threetimes greater than the primary surface area of the syringe; transferringgas from the syringe into a pulmonary function test device; andvalidating the pulmonary function test device based at least in part ona measurement of a volume of the gas transferred between the pulmonaryfunction test device and the syringe.
 2. The method of claim 1, wherein:the syringe is in thermal contact with a surface at least 10 .degree. C.above the room temperature for an elapsed time of at least 2 minutesbetween drawing ambient atmospheric gas and transferring gas from thesyringe; and the specific volume of gas within the syringe changes byless than 0.2% between drawing ambient atmospheric gas into the syringeand transferring gas from the syringe.
 3. The method of claim 1,wherein: the syringe is in direct sunlight for at least 2 minutesbetween drawing ambient atmospheric gas and transferring gas from thesyringe; and the specific volume of gas within the syringe changes byless than 0.2% between drawing ambient atmospheric gas into the syringeand transferring gas from the syringe.
 4. The method of claim 1, whereinthe pulmonary function test device is validated to perform a dynamiclung volume test.
 5. The method of claim 1, wherein the pulmonaryfunction test device is validated to perform an absolute lung volumetest.
 6. A device comprising: a processor; and a memory coupled with andreadable by the processor and storing therein a set of instructionswhich, when executed by the processor, causes the processor to: drawambient atmospheric gas having a room temperature into a syringe havinga housing defining a primary surface area of the syringe, a piston, anda heat transfer element coupled to the housing and having a surface areaat least three times greater than the primary surface area of thesyringe; transfer gas from the syringe into a pulmonary function testdevice; and validate the pulmonary function test device based at leastin part on a measurement of a volume of the gas transferred between thepulmonary function test device and the syringe.
 7. The device of claim6, wherein: the syringe is in thermal contact with a surface at least 10.degree. C. above the room temperature for an elapsed time of at least 2minutes between drawing ambient atmospheric gas and transferring gasfrom the syringe; and the specific volume of gas within the syringechanges by less than 0.2% between drawing ambient atmospheric gas intothe syringe and transferring gas from the syringe.
 8. The device ofclaim 6, wherein: the syringe is in direct sunlight for at least 2minutes between drawing ambient atmospheric gas and transferring gasfrom the syringe; and the specific volume of gas within the syringechanges by less than 0.2% between drawing ambient atmospheric gas intothe syringe and transferring gas from the syringe.
 9. The device ofclaim 6, wherein the pulmonary function test device is validated toperform a dynamic lung volume test.
 10. The device of claim 6, whereinthe pulmonary function test device is validated to perform an absolutelung volume test.
 11. A non-transitory, computer-readable mediumcomprising a set of instructions stored therein which, when executed bya processor, causes the processor to: draw ambient atmospheric gashaving a room temperature into a syringe having a housing defining aprimary surface area of the syringe, a piston, and a heat transferelement coupled to the housing and having a surface area at least threetimes greater than the primary surface area of the syringe; transfer gasfrom the syringe into a pulmonary function test device; and validate thepulmonary function test device based at least in part on a measurementof a volume of the gas transferred between the pulmonary function testdevice and the syringe.
 12. The non-transitory, computer-readable mediumof claim 11, wherein: the syringe is in thermal contact with a surfaceat least 10 .degree. C. above the room temperature for an elapsed timeof at least 2 minutes between drawing ambient atmospheric gas andtransferring gas from the syringe; and the specific volume of gas withinthe syringe changes by less than 0.2% between drawing ambientatmospheric gas into the syringe and transferring gas from the syringe.13. The non-transitory, computer-readable medium of claim 11, wherein:the syringe is in direct sunlight for at least 2 minutes between drawingambient atmospheric gas and transferring gas from the syringe; and thespecific volume of gas within the syringe changes by less than 0.2%between drawing ambient atmospheric gas into the syringe andtransferring gas from the syringe.
 14. The non-transitory,computer-readable medium of claim 11, wherein the pulmonary functiontest device is validated to perform a dynamic lung volume test.
 15. Thenon-transitory, computer-readable medium of claim 11, wherein thepulmonary function test device is validated to perform an absolute lungvolume test.